Antibiotic therapy for infectious hemodialysed patients in Bamako: Pharmacokinetic analyses and first improvement suggestions.

Infection which occurs in renal kidney failure patient have to be therapeutically managed immediately and the treatment must be aggressive to be quickly efficient. In Bamako (Mali). Posology adaptation cause a problem in nephrology, especially for the most common used antibiotics to care these infections. Drug dosage is not routinely performed in Bamako. The main objective of this work is to compare anthropometric, clinical and pharmacokinetic profiles and the clinical future between infected hemodialysis patients following an antibiotic therapy in Bamako and Lyon (hospital used as a reference). To reach these objectives, a preliminary punctual study of clinical pharmacokinetic of vancomycin were set up at Bamako, following the personalization therapeutics model from Lyon. Bamako patients' samples were imported to France and dosage analysis were performed at Lyon. BestDose software was used to view and compare complete pharmacokinetic profile. It includes for the first time, in routine, the 50 ml/mn of the renal function during dialyses for 58 patients: 31 for Bamako and 21 for Lyon. The residual concentration at the beginning of the dialysis session was compared. In Bamako, patients are younger, the renal failure is more severe and arteriovenous fistula are never set up, treatments are limited in dose and in duration; the residual concentration before the dialyses are too low; as a consequence, infections are rarely quickly reduced and more especially the death linked to these infections are more important (9 in Bamako versus 1 in Lyon). Urgent corrective measures have to be proposed: propose a conciliation between therapeutic requirements formulated within Lyon protocols and the financial ability of the patient, to promote arteriovenous fistula creation as soon as possible, and develop first dose strategy (unfortunately there is often only one dose): a more aggressive dose estimated from simulation profile performed in this study.

Crucial and Overlapping Roles of Six1 and Six2 in Craniofacial Development.

SIX1 and SIX2 encode closely related transcription factors of which disruptions have been associated with distinct craniofacial syndromes, with mutations in SIX1 associated with branchiootic syndrome 3 (BOS3) and heterozygous deletions of SIX2 associated with frontonasal dysplasia defects. Whereas mice deficient in Six1 recapitulated most of the developmental defects associated with BOS3, mice lacking Six2 function had no obvious frontonasal defects. We show that Six1 and Six2 exhibit partly overlapping patterns of expression in the developing mouse embryonic frontonasal, maxillary, and mandibular processes. We found that Six1 -/- Six2 -/- double-mutant mice were born with severe craniofacial deformity not seen in the Six1 -/- or Six2 -/- single mutants, including skull bone agenesis, midline facial cleft, and syngnathia. Moreover, whereas Six1 -/- mice exhibited partial transformation of maxillary zygomatic bone into a mandibular condyle-like structure, Six1 -/-Six2 +/- mice exhibit significantly increased penetrance of the maxillary malformation. In addition to ectopic Dlx5 expression at the maxillary-mandibular junction as recently reported in E10.5 Six1 -/- embryos, the E10.5 Six1 -/- Six2 +/- embryos showed ectopic expression of Bmp4, Msx1, and Msx2 messenger RNAs in the maxillary-mandibular junction. Genetically inactivating 1 allele of either Ednra or Bmp4 significantly reduced the penetrance of maxillary malformation in both Six1 -/- and Six1 -/- Six2 +/- embryos, indicating that Six1 and Six2 regulate both endothelin and bone morphogenetic protein-4 signaling pathways to pattern the facial structures. Furthermore, we show that neural crest-specific inactivation of Six1 in Six2 -/- embryos resulted in midline facial cleft and frontal bone agenesis. We show that Six1 -/- Six2 -/- embryos exhibit significantly reduced expression of key frontonasal development genes Alx1 and Alx3 as well as increased apoptosis in the developing frontonasal mesenchyme. Together, these results indicate that Six1 and Six2 function partly redundantly to control multiple craniofacial developmental processes and play a crucial neural crest cell-autonomous role in frontonasal morphogenesis.

Population modeling and simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of isoniazid in lungs.

Among first-line antituberculosis drugs, isoniazid (INH) displays the greatest early bactericidal activity (EBA) and is key to reducing contagiousness in treated patients. The pulmonary pharmacokinetics and pharmacodynamics of INH have not been fully characterized with modeling and simulation approaches. INH concentrations measured in plasma, epithelial lining fluid, and alveolar cells for 89 patients, including fast acetylators (FAs) and slow acetylators (SAs), were modeled by use of population pharmacokinetic modeling. Then the model was used to simulate the EBA of INH in lungs and to investigate the influences of INH dose, acetylator status, and M. tuberculosis MIC on this effect. A three-compartment model adequately described INH concentrations in plasma and lungs. With an MIC of 0.0625 mg/liter, simulations showed that the mean bactericidal effect of a standard 300-mg daily dose of INH was only 11% lower for FA subjects than for SA subjects and that dose increases had little influence on the effects in either FA or SA subjects. With an MIC value of 1 mg/liter, the mean bactericidal effect associated with a 300-mg daily dose of INH in SA subjects was 41% greater than that in FA subjects. With the same MIC, increasing the daily INH dose from 300 mg to 450 mg resulted in a 22% increase in FA subjects. These results suggest that patients infected with M. tuberculosis with low-level resistance, especially FA patients, may benefit from higher INH doses, while dose adjustment for acetylator status has no significant impact on the EBA in patients with low-MIC strains.

Study of relationship between volume of distribution and body weight application to amikacin.

Amikacin use is difficult because of its narrow therapeutic and its pharmacokinetic variability. This variability of amikacin is not well known. To adapt amikacin the physician assumes that there is a linear and continuous relation between the volume of distribution and the body weight. The objective of our study was to evaluate the relationship between the volume of distribution (Vd) and the body weight (BW) using a non parametric statistical analysis of dependence so called Z method. Retrospective pharmacokinetic population study and statistic analysis. 872 patients receiving intravenous amikacin. The volume of distribution was modelled using the Non Parametric Adaptive Grid algorithm (NPAG) for a two-compartment model with intravenous infusion. Z coefficient was performed to evaluate the relationships between Vd and BW. For the 872 patients (mean age of 73 ± 17 years) dispatched as follow 53 % female and 47 % male, the analysis of the statistical relationships by the non parametric Z analysis showed a scattered linkage between Vd and BW. For the whole population, the relationship between Vd and BW was not linear (regression analysis). Z analysis demonstrated that only for 80 % of patients there is a relationship between Vd and BW. For these patients, regression analysis give a significant adjustment of a linear model (r = 0.47, p < 0.001). In the whole studied population there is not a continuous and linear relationship between Vd estimated by NPAG and the BW. These results underline the difficulties to adapt doses of amikacin with only BW information.

[Inter-individual and intra-individual pharmacokinetic variability during teicoplanin therapy in geriatric patients]. / Variabilité pharmacocinétique inter- et intra-individuelle lors de traitements par teicoplanine chez les sujets âgés.

OBJECTIVES: The authors had for aim to assess the inter- and intra-individual variability of teicoplanin pharmacokinetic parameters in geriatric patients. METHODS: A cohort of 90 geriatric patients, treated with teicoplanin, was used to build two models describing the pharmacokinetics of teicoplanin, at the beginning and at the end of treatment respectively. RESULTS: The inter- and intra-individual variability of parameters were important as shown respectively by the coefficients of variation of pharmacokinetic parameters ranging from 125 to 694% and the half-life change during the treatment (by a factor of three to more than 30) for 60% of patients. CONCLUSIONS: The results revealed that elderly patients presented significant variability, which was only partly explained by the renal function. Therapeutic monitoring of teicoplanin in geriatric patients should be undertaken at the end of the loading dose and repeatedly during the maintenance phase to prevent over- or underexposure.

Guidelines for aminoglycoside use and applicability to geriatric patients.

OBJECTIVES: The authors had for objective to evaluate the applicability of AFSSAPS guidelines for aminoglycoside use to geriatric patients. METHODS: Theoretical doses and dosing regimens allowing reaching target concentrations in this population were calculated by applying a pharmacokinetic model to 30 geriatric patients treated by amikacin. RESULTS: The dose allowing reaching a maximum concentration of 60 mg/L was 1.217 mg on average. The time required to reach a blood concentration lower than or equal to 2.5mg/L was 62.5±70.4 hours. Forty-six percent of patients had a trough concentration greater than 2.5 mg/L, 48 hours after administration. For these patients, the time between critical minimum inhibitory concentration (MIC) and toxicity threshold concentration was 21.9±14.9 hours. CONCLUSION: Reaching a target concentration can be problematic in geriatric patients. It is frequently necessary to use dosing intervals greater than 48 hours. The effectiveness and safety of these regimens remain uncertain.

[Practical application of the charter of pharmaceutical sales visit]. / Application pratique de la charte de la visite médicale.

BACKGROUND: Visits from pharmaceutical representatives are controlled in France by regulations, but also by a Charter of good practice. The goal of this study was to measure compliance to the conditions of this charter by participating pharmaceutical companies. MATERIAL AND METHODS: An assessment grid was drafted to determine compliance to interdictions and obligations concerning the information provided during visits from pharmaceutical representatives. RESULTS: We studied 20 visits from pharmaceutical representatives. All of the documents and obligatory information were only provided in 5% of cases. During 80% of these meetings, the pharmaceutical representatives made a comparison with competitor's drugs, which was associated with negative remarks in 44% of cases. The pharmaceutical representatives promoted cases of use outside those, which had received marketing approval in 35%. Gifts or samples were offered at the end of these meetings in 20% of cases. Prohibited practices were observed in a total of 85% of cases. DISCUSSION: This study shows that meetings are respected by pharmaceutical representatives in terms of regulations related to donations. In opposite, there is a very low compliance concerning the proper use of the drug, whether to provide official documentation, to give information respectful of other pharmaceutical companies or to promote the proper use. CONCLUSION: Our results suggest that, at present hospital visits by pharmaceutical representatives do not respect the commitments made by the pharmaceutical industry, and do not make it possible to ensure that honest information is provided to favor the proper use of drugs.

[Relationship between benzodiazepines use and falls in the elderly: a multicenter study in three geriatric centers of a university hospital]. / Relation entre consommation de benzodiazépines et chutes en gériatrie : étude multicentrique dans trois établissements gériatriques d'un CHU.

INTRODUCTION: Benzodiazepines are widely used in the elderly, but may induce potentially severe iatrogenic events like falls. The analysis of their use is difficult because of the numerous molecules and dosages available. The aim of the present study is to build a tool to monitor their consumption and to evaluate the relation between this consumption and patient's falls reported in three geriatric institutions. METHODS: Conversion coefficients found in the literature allowed the expression of benzodiazepine action with a unique comparator: diazepam. Benzodiazepine consumption observed during 20 consecutive months was collected and weighted by hospital activity. A correlation between benzodiazepine consumption and the number of falls reported during the same period was researched. RESULTS: Benzodiazepine consumption expressed in milligrams of diazepam-equivalent per hospitalization day is significantly linked to the number of falls expressed during the same period (R=0.63; p<0.01). However, no statistical bound was found between monthly falls variations and monthly benzodiazepine consumption variations. These results corroborate others published studies: benzodiazepine consumptions are statistically linked to falls, but the reduction of this consumption is of poor predictive value, maybe because of the multifactorial nature of falls. DISCUSSION AND CONCLUSION: The expression of benzodiazepine consumption in diazepam-equivalent enables one to estimate the general exposition of patients and to compare the use of each molecule. The statistical link between this indicator and a major iatrogenic event like falls makes it a tool worth interest for both clinicians and pharmacists.

[Most frequent drug-related events detected by pharmacists during prescription analysis in a university hospital]. / Problèmes médicamenteux les plus fréquemment détectés par l'analyse pharmacothérapeutique des prescriptions dans un centre hospitalier universitaire.

PURPOSE: In France, the analysis of the prescriptions by a pharmacist in hospital is mandatory since 1991. However, for various reasons, this activity remained poorly developed and little research has been performed. Consequently, this activity suffers of a lack of visibility to hospital decision-makers and others health care professionals. The aim of this paper is to describe drugs related problems identified by pharmacist prescriptions analysis on a large number of orders in a large teaching hospital. This was done in order to highlight recurrent and preventable problems. METHODS: During 1 year period, drug related problems detected by pharmacists when performing prescription analysis were registered prospectively. RESULTS: Among 70,849 orders, 7073 drug related problems were registered. Most frequently detected drug related problems were: over dosages, especially with three drugs (zopiclone, zolpidem and acetaminophen) representing more than 10% of the pharmacist's interventions; optimization of drug administration especially with tablets that should not be crushed and intravenous to oral step-down therapy (7.5%); lack of conformity with consensus recommendations and contra-indications (12.8%); drug-drug interactions (11.6%) with a high proportion of absorption inhibition of one drug by another along the digestive tract; problems related to computerized physicians order entry (5.1%) appeared as an emerging phenomenon. CONCLUSION: These results should be used to reexamine hospital drug prescription policy. They prompt health care professionals to be aware about new medications errors potentially related to computerized prescription order entry. Finally, they invite to modify initial and continuous education programs of health care professionals.

[Interindividual pharmacokinetic variability in long-term antibiotherapy]. / Variabilité pharmacocinétique intra-individuelle et traitement antibiotique prolongé.

OBJECTIVE: The authors wanted to assess intraindividual pharmacokinetic variability, with a case of long-term amikacin therapy. DESIGN: A 92-year-old female patient, weighing 44kg, with renal failure, was treated by amikacin for 52 days. Her individual pharmacokinetic parameters were assessed 12 times in the course of therapy. The intraindividual variability of key parameters was quantified and compared with published interindividual variability. RESULTS: Intraindividual volume and clearance variability was measured at about one fourth to one third of the value observed for interindividual variability. Half-life intraindividual variability was almost equivalent to the interindividual variability: 24.5% versus 32%. CONCLUSIONS: The high pharmacokinetic variability observed has important potential clinical consequences. This case illustrates the need to ensure the effectiveness of treatment, to re-evaluate periodically the patient's status in order to take into account the intraindividual variability of pharmacokinetics parameters.

Erythropoietin induces a shift of muscle phenotype from fast glycolytic to slow oxidative.

Sedentary and trained rat groups were studied. Each of these groups was either erythropoietin or placebo treated. Erythropoietin treatment increased significantly all haematological parameters studied. Training per se failed to modify haematological parameters. In a second time, we studied the specific activity of several oxidative enzymes in three different muscles. In sedentary rats, erythropoietin treatment increased significantly the specific activities of cytochrome c oxidase and L-3-hydroxyacyl CoA dehydrogenase in the soleus and those of L-3-hydroxyacyl CoA dehydrogenase and phosphofructokinase in both locomotor muscles. Training increased the oxidative enzymes activities in all muscles studied. In trained rats, effects of erythropoietin and training on oxidative enzymes activities were additive. In all erythropoietin treated muscles, the expression of slow twitch myosin light chains and oxidative myosin heavy chains increased. A similar phenomenon took place in all trained groups for light chains and in placebo treated trained rats for heavy chains. In trained groups, the effects of the hormone and of training were additive. Our results suggest strongly that two different mechanisms are involved in the response of skeletal muscles to erythropoietin treatment and to endurance training and probably whole body endurance is affected by erythropoietin treatment by an increase of oxygenation of all tissues.

Revisiting nonlocal electron-energy transport in inertial-fusion conditions.

Correct modeling of the electron-energy transport is essential for inertial confinement fusion target design. Various transport models have been proposed in order to extend the validity of a hydrodynamical description into weakly collisional regimes, taking into account the nonlocality of the electron transport combined with the effects of self-generated magnetic fields. We have carried out new experiments designed to be highly sensitive to the modeling of the heat flow on the Ligne d'Intégration Laser facility, the prototype of the Laser Megajoule. We show that two-dimensional hydrodynamic simulations correctly reproduce the experimental results only if they include both the nonlocal transport and magnetic fields.

The humidification and filtration functions of the airways.

The mucociliary elevator is a highly evolved organ that humidifies inspired gases and protects the lungs from particulate, chemical, and microbiologic matter. Studies of disorders mucus and ciliary function have improved the understanding of this forgotten organ. The clinical implications of this understanding have yet to be explored.

Aminoglycoside nephrotoxicity.

The main constraints to the administration of aminoglycosides (AG) are risks of nephrotoxicity and ototoxicity, which can lead to renal and vestibular failure. AG accumulation in the kidney may be related to the dosing schedule. As a result, administration of larger doses on a less frequent basis may reduce the drug accumulation in the renal cortex. Many methods have been proposed to reduce AG nephrotoxicity. (1) Molecular modeling and analog synthesis could lead to intrinsically less toxic AG but this approach is time consuming and expensive. Protective approaches such as the co-administration of polyaspartic acid or defferoxamine appear to be very promising in clinical practice. (2) Population pharmacokinetic computer programs, used to control AG serum concentrations, are correct predictors of efficacy but the estimated concentrations in the second compartment are not reliable predictors of nephrotoxicity because they do not take into account non-linear processes such as the AG uptake in the renal cortex or the tubuloglomerular feedback. (3) Finally, modelling the AG nephrotoxicity with probabilistic approaches and/or with deterministic approaches seems to be very promising. These two approaches appear to be not competitive but very complementary in clinical practice. The probabilistic model can be used to predict nephrotoxicity at the beginning the treatment. The deterministic model can be used to simulate and control nephrotoxicity when it is already unfolding and the treatment must be given for a long period of time.

Pharmacokinetic modelling of cefotaxime and desacetylcefotaxime--a population study in 25 elderly patients.

OBJECTIVE: To develop a pharmacostatistical model to simultaneously characterise the pharmacokinetics of cefotaxime and its main metabolite, desacetylcefotaxime, in elderly patients. METHODS: Cefotaxime, 1 g, was infused three times daily to 25 elderly patients, 66-93 years old. Cefotaxime and desacetylcefotaxime plasma concentrations (289 and 304 samples, respectively), along with demographic and physiological characteristics, were analysed using a population approach. RESULTS: Cefotaxime pharmacokinetics was best described by a two-compartment open model in which desacetylcefotaxime was produced from the central compartment. The final parameter estimates were derived from simultaneous fit of parent/metabolite data. Cefotaxime clearance, mean 5.5 l/h, was positively influenced by body weight and serum protein concentration and negatively influenced by serum creatinine and age. In contrast, desacetylcefotaxime elimination was only decreased by age. The mean terminal half-lives of cefotaxime and desacetylcefotaxime were 1.7 h and 2.6 h, respectively. The stability and predictive performance of the final population pharmacokinetic model was assessed using 200 bootstrap samples of the original data. CONCLUSION: Cefotaxime and desacetylcefotaxime elimination decreased with increasing age above 60 years. This decreased elimination was related to individual characteristics that are typically related to renal function.

Clinical and pharmacological risk factors for acute graft-versus-host disease after paediatric bone marrow transplantation from matched-sibling or unrelated donors.

The aim of this study was to identify the risk factors for acute graft-versus-host disease (aGVHD) in children transplanted from a matched-sibling donor (MSD) or an unrelated donor (UD). In all, 87 children consecutively underwent allogeneic bone marrow transplantation (BMT) from MSD (n=36), and UD (n=51). GVHD prophylaxis included CsA alone (n=33) or with MTX (n=51). ATG was added in UD-BMT and thalassemic recipients. CsA whole-blood concentrations were measured by EMIT and the dosing regimen was monitored by Bayesian pharmacokinetic modelling. Trough blood concentration (TBC) during the first 2 weeks post transplantation was lower in children who developed grade II-IV aGVHD than those developing no GVHD or only grade I (57+/-9 vs 94+/-8 ng/ml, P=0.007), whereas peak blood concentration and area under concentration curve vs time were similar in both groups. TBC <85 ng/ml and 'use of MTX' were associated with aGVHD in MSD-SCT (P=0.003 and 0.007, respectively) as well as in UD-SCT (P=0.006 and 0.003). Donor age >or=8 years was significant only in MSD-BMT. Our results have shown the significant decisive role of pharmacological factors such as CSA TBC or use of MTX in the occurrence of GVHD in MSD as well as in UD paediatric BMT.

Relationship between CsA trough blood concentration and severity of acute graft-versus-host disease after paediatric stem cell transplantation from matched-sibling or unrelated donors.

In order to determine optimal CsA trough blood concentrations (TBC) in the early post transplantation period, we analysed relationships between TBC and acute graft-versus-host disease (aGVHD) in paediatric SCT. A total of 94 children consecutively underwent allogeneic stem cell transplantation (SCT) from: matched-sibling (MSD) (n=36), mismatched-related (MMRD) (n=3) and unrelated donors (UD) (n=55). GVHD prophylaxis usually included CsA alone or with methotrexate. Antithymocyte globulin was added in UD-SCT. TBC during the first weeks of post transplantation were estimated retrospectively by a Bayesian pharmacokinetic method and statistically associated with aGVHD. In MSD-SCT, the mean TBC during the first 2 weeks post transplantation were 42+/-10 and 90+/-7 ng/ml, respectively, in patients with grade II-IV and 0-I aGVHD (P=0.001). In SCT from UD and MMRD, TBC were 73+/-4 vs 95+/-8 ng/ml (P=0.284). For TBC >85 ng/ml, no patient developed grade II-IV aGVHD, 10 developed mild aGVHD and 30 had no aGVHD. For TBC <65 ng/ml, 7/11 patients receiving an MSD-SCT and 4/18 receiving an UD- or MMRD-SCT developed grade II-IV aGVHD. The mean TBC corresponding to each grade were: no GVHD: 101+/-10 ng/ml, mild: 77+/-11 ng/ml, moderate: 61+/-13 ng/ml, severe: 56+/-15 ng/ml (P <0.001). These results reveal a strong relationship between TBC during the early post transplantation period and the severity of aGVHD in paediatric SCT.

[PK/PD modeling of aminoglycoside nephrotoxicity]. / Un modèle PK/PD de la néphrotoxicité des aminoglycosides.

Aminoglycosides are bactericidial antibiotics with a serum concentration-dependent activity. They are mainly eliminated by the kidneys and the main difficulty arising in clinical use is their uptake by the renal cortex which leads to nephrotoxicity. An ototoxicity is also reported. We propose a PK/PD modelling of aminoglycoside nephrotoxicity which unifies more fourty years of physiological knowledge. This deterministic model successively describes the pharmacokinetics of aminoglycosides, their storage into renal cortex, their effect on renal cells, their consequences on the renal function through tubuloglomerular feedback and the changes in the serum concentrations of creatinine that is considered as a toxicity marker. The simulation of the model displays the leading effect of the shape and daily-time of administration schedule on the search for minimizing toxicity.

Generation of food-grade lactococcal starters which produce the lantibiotics lacticin 3147 and lacticin 481.

Transconjugant lactococcal starters which produce both lantibiotics lacticin 3147 and lacticin 481 were generated via conjugation of large bacteriocin-encoding plasmids. A representative of one of the resultant strains proved more effective at killing Lactobacillus fermentum and inhibiting the growth of Listeria monocytogenes LO28H than either of the single bacteriocin-producing parental strains, demonstrating the potential of these transconjugants as protection cultures for food safety applications.